The IFN consensus sequence binding protein (ICSBP/IRF-8), which belongs to the interferon[unreadable] regulatory factor family of transcription factors, is essential for a Thl immune response.[unreadable] ICSBP plays an important role in the host defense against microbial pathogens, but the exact[unreadable] roles of ICSBP in inflammation and chronic inflammatory diseases are still not clear. IL-10-/-[unreadable] mice, which develop colitis characterized by increased Thl cytokines, mimic many aspects of[unreadable] human Crohn's disease (CD). The importance of ICSBP in the development of colitis is shown[unreadable] by the lack of disease in ICSBP and IL-10 double knockout mice. In addition, ICSBP mRNA[unreadable] and protein are highly expressed in the colons of IL-10-/- mice with colitis, while expression[unreadable] of IL-12 and iNOS is significantly compromised in ICSBP/IL-10 double KO mice. In agreement[unreadable] with these results, patients with CD have significantly higher ICSBP expression than normal[unreadable] individuals. ICSBP is active in several loci. ICSBP interacts with TRAF6 in the TLR4 pathway,[unreadable] and binds to ISRE sites in the iNOS and IL-12 p40 promoters, activating the expression of[unreadable] these genes. In addition, we find that ICSBP is ubiquitinated by the E3 ligase Cbl, resulting in[unreadable] its degradation by the proteasome. To expore ICSBP as a suitable target for therapy in CD,[unreadable] this proposal is structured around three aims: 1) We will analyze the regulation of ICSBP[unreadable] expression in macrophages and dendritic cells activated with various TLR and NOD2 ligands.[unreadable] In addition, we will define the role of ICSBP in the generation of regulatory T cells. 2) We will[unreadable] define the function of Cbl in the control of Thl immune immune response and analyze the[unreadable] role of Cbl in the development of colitis. 3) We will define the therapeutic effects of TLR4 and[unreadable] ICSBP inhibition by cell-permeable peptide reagent in vivo in murine colitis models. These[unreadable] studies will advance our understanding the role of ICSBP in the mucosal immune response,[unreadable] and may identify ICSBP as a new target for therapy in CD.